PROJECT SUMMARY Tuberculosis (TB) remains the single largest infectious killer of adults worldwide, and development of drug- resistant strains is a public health crisis. As an alternative to oral and IV delivery in TB treatment, direct lung delivery via dry powder inhaler (DPI) can be used to achieve shorter treatment regimens, overcome drug resistance, and rapidly reduce transmission rates. However, traditional, low-potency DPIs are not optimized to meet the challenges of TB therapy (high doses, narrow therapeutic indices, and delivery of labile molecules). Next-generation DPIs must exhibit efficient powder aerosolization, promote drug stability, and ensure reproducible lung deposition independent of lung function. This must occur within the cost-constraints of TB, which necessitates a systematic and streamlined development approach. It is hypothesized that high-dose, carrier-free dry powders must exhibit certain properties for aerosolization to be achieved, and that the pairing of these properties to the appropriate device dispersion mechanism will enable inspiratory flow-independent lung deposition. Over the course of three years, this hypothesis will be tested through a comprehensive analysis of critical physicochemical characteristics of micronized drug powders in relation to aerosolization, application of these findings to a challenging monoclonal antibody model, and through a study of the behavior of respirable drug particles in a variety of device and inhalation settings. The empirical data derived through these studies will be used to model the relationship between particle cohesion, device dispersion, and aerosolization to further optimize existing high dose DPIs and predict performance of novel DPIs. The training environment (University of Texas) will fully support this study by providing the necessary resources for particle engineering, small molecule and biologic analysis, and aerosol testing. In addition to promising scientific insights, the proposed study will provide extensive training in powder characterization techniques, device prototyping, small molecule and biological processing and analysis, and mathematical modeling that are necessary for progression to an independent research career in the pharmaceutical sciences. The overall significance of this study is that it is a translational research approach that links a mechanistic understanding of respirable particle behavior to the pre- clinical development of targeted and cost-effective therapies for devastating pulmonary diseases like tuberculosis. The systematic approach will greatly streamline the development of future small molecule and biopharmaceutical inhaled therapies and reduce the risk of pre-clinical to clinical translation.